Thumbnail - download.e-bookshelf.de · 1.2 From Biosynthesis to total Synthesis: Strategies toward the Natural Product Chemical Space, 10 1.2.1 the Chemical Space of Natural Products,

Thumbnailjpg

From Biosynthesis to total synthesis


strategies and tactics for natural Products

Edited by

alexandros l ZograFosAristotle University of Thessaloniki Greece

Copyright copy 2016 by John Wiley amp Sons Inc All rights reserved

Published by John Wiley amp Sons Inc Hoboken New JerseyPublished simultaneously in Canada

No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photocopying recording scanning or otherwise except as permitted under Section 107 or 108 of the 1976 United States Copyright Act without either the prior written permission of the Publisher or authorization through payment of the appropriate per‐copy fee to the Copyright Clearance Center Inc 222 Rosewood Drive Danvers MA 01923 (978) 750‐8400 fax (978) 750‐4470 or on the web at wwwcopyrightcom Requests to the Publisher for permission should be addressed to the Permissions Department John Wiley amp Sons Inc 111 River Street Hoboken NJ 07030 (201) 748‐6011 fax (201) 748‐6008 or online at httpwwwwileycomgopermissions

Limit of LiabilityDisclaimer of Warranty While the publisher and author have used their best efforts in preparing this book they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifically disclaim any implied warranties of merchantability or fitness for a particular purpose No warranty may be created or extended by sales representatives or written sales materials The advice and strategies contained herein may not be suitable for your situation You should consult with a professional where appropriate Neither the publisher nor author shall be liable for any loss of profit or any other commercial damages including but not limited to special incidental consequential or other damages

For general information on our other products and services or for technical support please contact our Customer Care Department within the United States at (800) 762‐2974 outside the United States at (317) 572‐3993 or fax (317) 572‐4002

Wiley also publishes its books in a variety of electronic formats Some content that appears in print may not be available in electronic formats For more information about Wiley products visit our web site at wwwwileycom

Library of Congress Cataloging‐in‐Publication Data

Names Zografos Alexandros L editorTitle From biosynthesis to total synthesis strategies and tactics for natural products edited by Alexandros L ZografosDescription Hoboken New Jersey John Wiley amp Sons Inc [2016] | Includes bibliographical references and indexIdentifiers LCCN 2015037375 (print) | LCCN 2015047240 (ebook) | ISBN 9781118751732 (cloth) | ISBN 9781118753569 (Adobe PDF) | ISBN 9781118753637 (ePub)Subjects LCSH Organic compoundsndashSynthesis | BiosynthesisClassification LCC QD262 F76 2016 (print) | LCC QD262 (ebook) | DDC 57245ndashdc23LC record available at httplccnlocgov2015037375

Set in 1012pt Times by SPi Global Pondicherry India

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

Dedicated to my mother father and wife

LIST OF CONTRIBUTORS xiii

PREFACE xv

1 From Biosyntheses to Total Syntheses An Introduction 1Bastien Nay and Xu‐Wen Li

11 From Primary to Secondary Metabolism the Key Building Blocks 1111 Definitions 1112 Energy Supply and Carbon Storing at the Early Stage

of Metabolisms 1113 Glucose as a Starting Material toward Key Building Blocks

of the Secondary Metabolism 1114 Reactions Involved in the Construction of Secondary Metabolites 3115 Secondary Metabolisms 4

12 From Biosynthesis to total Synthesis Strategies toward the Natural Product Chemical Space 10121 the Chemical Space of Natural Products 10122 the Biosynthetic Pathways as an Inspiration

for Synthetic Challenges 11123 the Science of total Synthesis 14124 Conclusion a Journey in the Future of total Synthesis 16

References 16

SECTION I ACETATE BIOSYNTHETIC PATHWAY 19

2 Polyketides 21Franccediloise Schaefers Tobias A M Gulder Cyril Bressy Michael Smietana Erica Benedetti Stellios Arseniyadis Markus Kalesse and Martin Cordes

21 Polyketide Biosynthesis 21211 Introduction 21212 assembly of acetateMalonate‐Derived Metabolites 23213 Classification of Polyketide Biosynthetic Machineries 23214 Conclusion 39

References 40

CONTENTS

viii CoNtENtS

22 Synthesis of Polyketides 44221 asymmetric alkylation Reactions 44222 applications of asymmetric alkylation Reactions in total Synthesis

of Polyketides and Macrolides 60References 8323 Synthesis of Polyketides‐Focus on Macrolides 87

231 Introduction 87232 Stereoselective Synthesis of 13‐Diols asymmetric aldol Reactions 88233 Stereoselective Synthesis of 13‐Diols asymmetric Reductions 106234 application of Stereoselective Synthesis of 13‐Diols in

the total Synthesis of Macrolides 117235 Conclusion 126

References 126

3 Fatty Acids and Their Derivatives 130Anders Vik and Trond Vidar Hansen

31 Introduction 13032 Biosynthesis 130

321 Fatty acids and Lipids 130322 Polyunsaturated Fatty acids 134323 Mediated oxidations of ω‐3 and ω‐6 Polyunsaturated

Fatty acids 13533 Synthesis of ω‐3 and ω‐6 all‐Z Polyunsaturated Fatty acids 140

331 Synthesis of Polyunsaturated Fatty acids by the Wittig Reaction or by the Polyyne Semihydrogenation 140

332 Synthesis of Polyunsaturated Fatty acids via Cross Coupling Reactions 143

34 applications in total Synthesis of Polyunsaturated Fatty acids 145341 Palladium‐Catalyzed Cross Coupling Reactions 145342 Biomimetic transformations of Polyunsaturated Fatty acids 149343 Landmark total Syntheses 153344 Synthesis of Leukotriene B

5 158

35 Conclusion 160acknowledgments 160References 160

4 Polyethers 162Youwei Xie and Paul E Floreancig


421 Ionophore antibiotics 162422 Marine Ladder toxins 165423 annonaceous acetogenins and terpene Polyethers 165

43 Epoxide Reactivity and Stereoselective Synthesis 166431 Regiocontrol in Epoxide‐opening Reactions 166432 Stereoselective Epoxide Synthesis 172

44 applications to total Synthesis 176441 acid‐Mediated transformations 176442 Cascades via Epoxonium Ion Formation 179443 Cyclizations under Basic Conditions 181444 Cyclization in Water 182

45 Conclusions 183References 184

CoNtENtS ix

SECTION II MEVALONATE BIOSYNTHETIC PATHWAY 187

5 From Acetate to Mevalonate and Deoxyxylulose Phosphate Biosynthetic Pathways An Introduction to Terpenoids 189Alexandros L Zografos and Elissavet E Anagnostaki

51 Introduction 18952 Mevalonic acid Pathway 19153 Mevalonate‐Independent Pathway 19254 Conclusion 194References 194

6 Monoterpenes and Iridoids 196Mario Waser and Uwe Rinner


621 acyclic Monoterpenes 197622 Cyclic Monoterpenes 197623 Iridoids 200624 Irregular Monoterpenes 202

63 asymmetric organocatalysis 203631 Introduction and Historical Background 204632 Enamine Iminium and Singly occupied Molecular

orbital activation 207633 Chiral (Broslashnsted) acids and H‐Bonding Donors 213634 Chiral BroslashnstedLewis Bases and Nucleophilic Catalysis 218635 asymmetric Phase‐transfer Catalysis 220

64 organocatalysis in the total Synthesis of Iridoids and Monoterpenoid Indole alkaloids 225641 (+)‐Geniposide and 7‐Deoxyloganin 226642 (ndash)‐Brasoside and (ndash)‐Littoralisone 227643 (+)‐Mitsugashiwalactone 229644 alstoscholarine 229645 (+)‐aspidospermidine and (+)‐Vincadifformine 230646 (+)‐Yohimbine 230

65 Conclusion 231References 231

7 Sesquiterpenes 236Alexandros L Zografos and Elissavet E Anagnostaki

71 Biosynthesis 23672 Cycloisomerization Reactions in organic Synthesis 244

721 Enyne Cycloisomerization 245722 Diene Cycloisomerization 257

73 application of Cycloisomerizations in the total Synthesis of Sesquiterpenoids 266731 Picrotoxane Sesquiterpenes 266732 aromadendrane Sesquiterpenes Epiglobulol 267733 CubebolndashCubebenes Sesquiterpenes 267734 Ventricos‐7(13)‐ene 270735 Englerins 271736 Echinopines 271737 Cyperolone 273

x CoNtENtS

738 Diverse Sesquiterpenoids 27674 Conclusion 276References 276

8 Diterpenes 279Louis Barriault

81 Introduction 27982 Biosynthesis of Diterpenes Based on Cationic Cyclizations

12‐Shifts and transannular Processes 27983 Pericyclic Reactions and their application in the Synthesis

of Selected Diterpenoids 284831 Dielsndashalder Reaction and Its application in the total

Synthesis of Diterpenes 284832 Cascade Pericyclic Reactions and their application in the total

Synthesis of Diterpenes 29184 Conclusion 293

References 294

9 Higher Terpenes and Steroids 296Kazuaki Ishihara

91 Introduction 29692 Biosynthesis 29693 Cascade Polyene Cyclizations 303

931 Diastereoselective Polyene Cyclizations 303932 ldquoChiral proton (H+)rdquo‐Induced Polyene Cyclizations 304933 ldquoChiral Metal Ionrdquo‐Induced Polyene Cyclizations 308934 ldquoChiral Halonium Ion (X+)rdquo‐Induced Polyene Cyclizations 313935 ldquoChiral Carbocationrdquo‐Induced Polyene Cyclizations 319936 Stereoselective Cyclizations of Homo(polyprenyl)arene

analogs 31994 Biomimetic total Synthesis of terpenes and Steroids through

Polyene Cyclization 31995 Conclusion 328

References 328

SECTION III SHIKIMIC ACID BIOSYNTHETIC PATHWAY 331

10 Lignans Lignins and Resveratrols 333Yu Peng

101 Biosynthesis 3331011 Primary Metabolism of Shikimic acid and aromatic

amino acids 3331012 Lignans and Lignin 335

102 auxiliary‐assisted C(sp3)ndashH arylation Reactions in organic Synthesis 336

103 FriedelndashCrafts Reactions in organic Synthesis 344104 total Synthesis of Lignans by C(sp3)H arylation Reactions 353105 total Synthesis of Lignans and Polymeric Resveratrol by

FriedelndashCrafts Reactions 357106 Conclusion 375References 375

CoNtENtS xi

SECTION IV MIXED BIOSYNTHETIC PATHWAYSndash THE STORY OF ALKALOIDS 381

11 Ornithine and Lysine Alkaloids 383Sebastian Brauch Wouter S Veldmate and Floris P J T Rutjes

111 Biosynthesis of l‐ornithine and l‐Lysine alkaloids 3831111 Biosynthetic Formation of alkaloids

Derived from l‐ornithine 3831112 Biosynthetic Formation of alkaloids

Derived from l‐Lysine 388112 the asymmetric Mannich Reaction in organic Synthesis 392

1121 Chiral amines as Catalysts in asymmetric Mannich Reactions 3941122 Chiral Broslashnsted Bases as Catalysts in asymmetric

Mannich Reactions 3981123 Chiral Broslashnsted acids as Catalysts in asymmetric

Mannich Reactions 4041124 organometallic Catalysts in asymmetric Mannich Reactions 4081125 Biocatalytic asymmetric Mannich Reactions 413

113 Mannich and Related Reactions in the total Synthesis of l‐Lysine‐ and l‐ornithine‐Derived alkaloids 414


12 Tyrosine Alkaloids 431Uwe Rinner and Mario Waser

121 Introduction 431122 Biosynthesis of tyrosine‐Derived alkaloids 431

1221 Phenylethylamines 4311222 Simple tetrahydroisoquinoline alkaloids 4331223 Modified Benzyltetrahydroisoquinoline alkaloids 4331224 Phenethylisoquinoline alkaloids 4361225 amaryllidaceae alkaloids 4381226 Biosynthetic overview of tyrosine‐Derived alkaloids 442

123 arylndasharyl Coupling Reactions 4421231 Copper‐Mediated arylndasharyl Bond Forming Reactions 4431232 Nickel‐Mediated arylndasharyl Bond Forming Reactions 4461233 Palladium‐Mediated arylndasharyl Bond Forming Reactions 4471234 transition Metal‐Catalyzed Couplings of Nonactivated

aryl Compounds 450124 Synthesis of tyrosine‐Derived alkaloids 456

1241 Synthesis of Modified Benzyltetrahydroisoquinoline alkaloids 4561242 Synthesis of Phenethylisoquinoline alkaloids 4601243 Synthesis of amaryllidaceae alkaloids 462


13 Histidine and Histidine‐Like Alkaloids 473Ian S Young

131 Introduction 473132 Biosynthesis 473133 atom Economy and Protecting‐Group‐Free Chemistry 480

xii CoNtENtS

134 Challenging the Boundaries of Synthesis PIas 488135 Conclusion 497References 499

14 Anthranilic AcidndashTryptophan Alkaloids 502Zhen‐Yu Tang

141 Biosynthesis 502142 Divergent SynthesisndashCollective total Synthesis 508143 Collective total Synthesis of tryptophan‐Derived alkaloids 510

1431 Monoterpene Indole alkaloids 5101432 Bisindole alkaloids 512

References 517

15 Future Directions of Modern Organic Synthesis 519Jakob Pletz and Rolf Breinbauer

151 Introduction 519152 Enzymes in organic Synthesis Merging total

Synthesis with Biosynthesis 520153 Engineered Biosynthesis 526154 Diversity‐oriented Synthesis Biology‐oriented Synthesis

and Diverted total Synthesis 5331541 Diversity‐oriented Synthesis 5351542 Biology‐oriented Synthesis 5361543 Diverted total Synthesis 539


INDEX 548

Elissavet E Anagnostaki Department of Chemistry Laboratory of Organic Chemistry Aristotle University of Thessaloniki Thessaloniki Greece and Research and Development Department Pharmathen SA Thessaloniki Greece

Stellios Arseniyadis School of Biological and Chemical Sciences Queen Mary University of London London United Kingdom

Louis Barriault Department of Chemistry University of Ottawa Ottawa Ontario Canada

Erica Benedetti Laboratoire de Chimie et Biochimie et Pharmacologiques et Toxicologiques CNRS-Universiteacute Paris Descartes Faculteacute des Sciences Fondamentales et Biomeacutedicales Paris France

Sebastian Brauch Institute for Molecules and Materials Radboud University Nijmegen Nijmegen The Netherlands

Rolf Breinbauer Institute of Organic Chemistry Technische Universitaumlt Graz Graz Austria

Cyril Bressy Aix Marseille Universiteacute Centrale Marseille CNRS Marseille France

Martin Cordes Institute for Organic Chemistry and Center of Biomolecular Drug Research (BMWZ) Leibniz Universitaumlt Hannover Hannover Germany and Helmholtz Center for Infection Research (HZI) Hannover Germany

Paul E Floreancig Department of Chemistry Chevron Science Center University of Pittsburgh Pittsburgh PA USA

Tobias A M Gulder Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM) Biosystems Chemistry Technische Universitaumlt Muumlnchen Munich Germany

Trond Vidar Hansen School of Pharmacy University of Oslo Oslo Norway

Kazuaki Ishihara Department of Biotechnology Graduate School of Engineering Nagoya University Nagoya Japan

Markus Kalesse Institute for Organic Chemistry and Center of Biomolecular Drug Research (BMWZ) Leibniz Universitaumlt Hannover Hannover Germany and Helmholtz Center for Infection Research (HZI) Hannover Germany

Xu‐Wen Li Shanghai Institute of Material Medica Chinese Academy of Science Shanghai China

Bastien Nay Museacuteum National drsquoHistoire Naturelle and CNRS (UMR 7245) Uniteacute Moleacutecules de Communication et Adaptation des Microorganismes Paris France

Yu Peng State Key Laboratory of Applied Organic Chemistry Lanzhou University Lanzhou China

Jakob Pletz Institute of Organic Chemistry Technische Universitaumlt Graz Graz Austria

Uwe Rinner Institute of Organic Chemistry Johannes Kepler University Linz Linz Austria and Department of Chemistry College of Science Sultan Qaboos University Muscat Oman

Floris P J T Rutjes Institute for Molecules and Materials Radboud University Nijmegen Nijmegen The Netherlands

LIST oF CoNTRIBUToRS

xiv LIST OF CONTRIBUTORS

Franccediloise Schaefers Department of Chemistry and Center for Integrated Protein Science Munich (CIPSM) Biosystems Chemistry Technische Universitaumlt Muumlnchen Munich Germany

Michael Smietana Institut des Biomoleacutecules Max Mousseron CNRS Universiteacute de Montpellier ENSCM France

Zhen‐Yu Tang Department of Pharmaceutical Engineering College of Chemistry and Chemical Engineering Central South University Changsha China

Wouter S Veldmate Institute for Molecules and Materials Radboud University Nijmegen Nijmegen The Netherlands

Anders Vik School of Pharmacy University of Oslo Oslo Norway

Mario Waser Institute of Organic Chemistry Johannes Kepler University Linz Linz Austria

Youwei Xie Max‐Planck‐Institut fuumlr Kohlenforschung Muumllheim Germany

Ian S Young Bristol‐Myers Squibb Company Chemical Development New Brunswick NJ USA

Alexandros L Zografos Department of Chemistry Laboratory of Organic Chemistry Aristotle University of Thessaloniki Thessaloniki Greece

There is pleasure in the pathless woodsthere is rapture in the lonely shore

there is society where none intrudesby the deep sea and music in its roar

I love not Man the less but Nature moreLord Byron

Preface

The first time I came across with the idea of editing a book that merges selected chapters of biosynthesis and total synthesis was when I was teaching postgraduate courses of natural product synthesis at Aristotle University of Thessaloniki This period I realized that the best way to teach youngsters synthesis was to start from the very origin of inspiration nature and its tools biosynthesis

Over the last decades biosynthesis is filling our gaps of understanding the complex mechanisms of nature and pro-vides useful sources of inspiration not only in the way natural products can be synthesized but also by directing synthetic chemists in developing atom‐economical efficient synthetic methods Several are the examples that mimic biosynthetic guidelines from modern iterative alkylations and aldol reactions to CH oxidations that compile nowadays the modern toolbox of organic synthesis

The handed book is constructed in the logic of presenting the parallel development of biosynthesis and organic meth-odology and how these can be applied in efficient syntheses of natural products The book is divided into four sections each representing the four major biosynthetic pathways of natural products namely acetate mevalonate shikimate biosynthetic pathways and the mixed biosynthetic pathways

of alkaloids These sections are divided into chapters that represent selected classes of natural products for example lipids sesquiterpenoids lignans etc Each of these chapters is further divided into three distinct subchapters (a) biosyn-thesis (b) methodological section and (c) application of the described methodology in the total synthesis of the described family of natural products By this way the readers can be focused in the direct comparison between biosyn-theses and the developed methodologies to construct the crucial for each class of natural product carbon bonds Although the book as it develops is focused on presenting the power of biosynthesis and how this power can be applied in providing inspiration for the efficient synthesis of natural products it was not the authors will to present only biomi-metic total syntheses but rather to exploit the modern synthetic methodologies and recognize their disabilities for further improvement

Of course this book will not have been realized without the excellent work of renowned scientists worldwide working either in the field of biosynthesis or total synthesis who collected the existing knowledge on biosynthesis analyzed the existing modern methodologies and presented a bouquet of selected total syntheses Throughout our

xvi PrEfACE

endeavor to complete this book I learned many things from their expertise but I also realized that only with tight collab-orations you can build long‐lasting friendships I would like to thank them all once again for their trust and effort to complete this book We all hope that the current work will contribute to a better understanding of the current status of

organic chemistry and to the discovery of novel strategies and tactics for the synthesis of natural products

Alexandros L ZografosSeptember 2015

Thessaloniki Greece

From Biosynthesis to Total Synthesis Strategies and Tactics for Natural Products First Edition Edited by Alexandros L Zografoscopy 2016 John Wiley amp Sons Inc Published 2016 by John Wiley amp Sons Inc

11 FROM PRIMARY TO SECONDARY METABOLISM THE KEY BUILDING BLOCKS

111 Definitions

The primary and secondary metabolisms are traditionally distinguished by their distribution and utility in the living organism network Primary metabolites include carbohyshydrates lipids nucleic acids and proteins (or their amino acid constituents) and are shared by all living organisms on Earth They are transformed by common pathways which are studied by biochemistry (Fig 11) Secondary metabo-lites are structurally diverse compounds usually produced by a limited number of organisms which synthesize them for a special purpose like defense or signaling through specific biosynthetic pathways They are studied by natural product chemistry This distinction is not always so obvious and some compounds can be studied in the context of both primary and secondary metabolisms This is especially true nowadays with the use of genetic and biomolecular tools which tend to make natural product sciences more and more integrative However an important point to remember is that the primary metabolism furnishes key building blocks to the secondary metabolism It would be difficult to describe in detail the full biosynthetic pathshyways in this section We tried to organize the discussion as a vade mecum synthetically gathering information from extremely useful sources which will be cited at the end of this chapter

112 Energy Supply and Carbon Storing at the Early Stage of Metabolisms

The sunlight is essential to life except in some part of the deep oceans It provides energy for plant photosynthesis that splits molecules of water into protons and electrons and releases O

2 (Scheme 11) A proton gradient inside the plant

chloroplasts then drags a transmembrane ATP synthase comshyplex that produces adenosine triphosphate (ATP) while elecshytrons released from water are transferred to the coenzyme reducer nicotinamide adenine dinucleotide phosphate hydride (NADPH) A major function of chloroplasts is to fix CO

2 as a combination to ribulose‐15‐bisphosphate (RuBP)

performed by RuBP carboxylase (rubisco) forming an instable ldquoC

6rdquo β‐ketoacid This is cleaved into two molecules

of 3‐phosphoglycerate (3‐PGA) which is then reduced into 3‐phosphoglyceraldehyde (3‐PGAL a ldquoC

3rdquo triose phosshy

phate) during the Calvin cycle This is one of the major metabolites in the biosynthesis of carbohydrates like glucose and a biochemical mean for storing and retaining carbon atoms in the living cells

113 Glucose as a Starting Material Toward Key Building Blocks of the Secondary Metabolism

Glucose‐6‐phosphate arises from the phosphorylation of glucose It is the starting material of glycolysis an important process of the primary metabolism which consists in eight enzymatic reactions leading to pyruvic acid (PA)

FROM BIOSYNTHESES TO TOTAL SYNTHESES AN INTRODUCTION

Bastien Nay1 and Xu‐Wen Li2

1

1 Museacuteum National drsquoHistoire Naturelle and CNRS (UMR 7245) Uniteacute Moleacutecules de Communication et Adaptation des Microorganismes Paris France2 Shanghai Institute of Material Medica Chinese Academy of Science Shanghai China

2 FROm BIOSyNTHESES TO TOTAL SyNTHESES AN INTRODuCTION

(Scheme 12) Important intermediates for the secondary metabolism are produced during glycolysis Glucose glucose‐6‐phosphate and fructose‐6‐phosphate can be converted to other hexoses and pentoses that can be oligoshymerized and enter in the composition of heterosides Additionally fructose‐6‐phosphate connects the pentose

phosphate pathway leading to erythrose‐4‐phosphate toward shikimic acid which is a key metabolite in the biosynthesis of aromatic amino acids (phenylalanine tyrosine or C

6C

3

units) and C6C

1 phenolic compounds The next important

intermediate in glycolysis is 3‐PGAL which can be redishyrected toward methylerythritol‐4‐phosphate (mEP) in the

Primary metabolism Secondary metabolism

The field ofbiochemistry

The field ofnatural product

chemistry

Essential toliving organisms

Essential to theproducer organisms

under particularconditions

Nucleic acids (DNARNA) carbohydrates

lipids amino acidspeptides and proteins

Alkaloids terpenespolyketides

polyphenols andtheir heterosidic form

Biological effects(defense signaling)

Biosyntheticpathways

Main compoundclasses

FIGURE 11 Primary versus secondary metabolisms

PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+

Thylakoidcompartment

Chloroplaststroma

Thylakoidmembrane

(a) Light dependent process

(b) Light independent process

CO2

RuBP

Rubisco

Unstable β-ketoacid3-PGA 13-diPGA

ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)

trioses tetroses pentoses hexoses (eg glucose) heptoses

Chloroplaststroma

CH2OPO32ndash

CH2OPO32ndash CH2OPO3

2ndash


2ndash CH2OPO32ndash

CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol

SCHEME 11 The photosynthetic machinery (PS‐I and PS‐II photosystems I and II)

FROm PRImARy TO SECONDARy mETABOLISm THE KEy BuILDING BLOCKS 3

chloroplast mEP is a starting block in the biosynthesis of terpenes through C

5 isoprene units (isopentenyl diphosphate

(IPP) and dimethylallyl diphosphate (DmAPP)) especially those in C

10 C

20 and C

40 terpenes 3‐PGA is a precursor of

serine and other amino acids while phosphoenolpyruvate (PEP) the precursor of PA is also an intermediate toward the previously mentioned shikimic acid Lastly PA is not only a precursor of the fundamental ldquoC

2rdquo acetyl coenzyme A

(AcCoA) unit but also an intermediate toward aliphatic amino acids and mEP

AcCoA is the building block of fatty acids polyketides and mevalonic acid (mVA) a cytosolic precursor of the C

5 isoprene units for the biosynthesis of terpenes in the

C15

and C30

series (mind it is different from the mEP pathway in product and in cell location) Finally AcCoA enters the citric acid or Krebs cycle which leads to several precursors of amino acids These are oxaloacetic acid precursor of aspartic acid through transamination (thus toward lysine as a nitrogenated C

5N linear unit and methishy

onine as a methyl supplier) and 2‐oxoglutaric acid preshycursor of glutamic acid (and subsequent derivatives such as ornithine as a nitrogenated C

4N linear unit) All these

amino acids are key precursors in the biosynthesis of many alkaloids

114 Reactions Involved in the Construction of Secondary Metabolites

most reactions occurring in the living cells are performed by specialized enzymes which have been classified in an intershynational nomenclature defined by an enzyme commission (EC) number There are six classes of enzymes depending on the biochemical reaction they catalyze EC‐1 oxidoreducshytases (catalyzing oxidoreduction reactions) EC‐2 transfershyases (catalyzing the transfer of functional groups) EC‐3 hydrolases (catalyzing hydrolysis) EC‐4 lyases (breaking bonds through another process than hydrolysis or oxidation leading to a new double bond or a new cycle) EC‐5 isomershyases (catalyzing the isomerization of a molecule) and EC‐6 ligases (forming a covalent bond between two molecules) many subclasses of these enzymes have been described depending on the type of atoms and functional groups involved in the reaction and if any on the cofactor used in this reaction For example several cofactors can be used by dehydrogenases like NAD(P)NAD(P)H FADFADH

2 or

FmNFmNH2 For a description of this classification the

reader can refer to specialized Internet websites like ExplorEnz [1] What is important to realize is that most enzymes are substrate specific and have been selected during

CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP

C10 C20 and C40 terpenes

CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA

C15 and C30 terpenes

Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate

Fructose-6-phosphate

Erythrose-4-phosphate

3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5

Shikimic acid Oxaloaceticacid

2-Oxoglutaricacid

MET

THR

PRO

ARGORN

Alkaloids Alkaloids Alkaloids Alkaloids

Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo

(Indole)C2NC6C3C6C2N C6C1

Pentosephosphatepathway

SCHEME 12 The building block chart involving glycolysis and the Krebs cycle


evolution to perform specific transformations making natural products with often and yet unknown functions

Secondary metabolites arise from specific biosynthetic pathways which use the previously defined building blocks The bunch of organic reactions involved in these biosynshytheses allows the construction of natural product frameshyworks which are finally diversified through ldquodecorationrdquo steps (Scheme 13) It is not the purpose of this introductive chapter to describe in detail all biosynthetic pathways and the reader can refer to excellent books and articles which have been published elsewhere [2 3]

The reactions involved in the construction of natural product skeletons will be described later for representative classes of compounds The identification of the building block footprint in the natural product skeleton will be emphasized as much as possible sometimes referring to biogenetic speculations [4] After the framework construction the decoration steps will involve as diverse reactions as aliphatic CH oxidations (eg involving a cytochrome P

450 oxygenase) occasionally triggering a

rearrangement heteroatom alkylations (eg methylation by S‐adenosylmethionine) or allylation (by DmAPP) esterifications heteroatom or C‐glycosylations (leading to heterosides) radical couplings (especially for phenols) alcohol oxidations or ketone reductions amineketone transaminations alkene dihydroxylations or epoxidations oxidative halogenations BaeyerndashVilliger oxidations and further oxygenation steps At the end of the biosynthesis such transformations may totally hide the primary building block origin of natural products

115 Secondary Metabolisms

1151 Polyketides Polyketides (or polyacetates) are issued from the oligomerization of C

2 acetate units performed

by polyketide synthases (PKS) and leading to (C2)

n linear

intermediates [5 6] If the (C2)

n intermediates arise from

successive Claisen reactions performed by ketosynthase

domains (KS in nonreducing PKS) a highly reactive poly‐ β‐ketoacyl intermediate H(CH

2CO)

nOH is formed

leading to phenolic and aromatic products through further intramolecular Claisen condensations Furthermore highly reducing PKSs are made of specialized enzymatic subunits working in line or iteratively to functionalize each C

2 linker

bond as CH(OH)CH2 (by ketoreductases (KR)) then as

HCCH (by dehydratases (DH)) and as CH2CH

2 (by enoyl

reductases (ER)) leading to a high degree of functionalization of the final product (Fig 12) By these iterative sequences highly reduced polyketides which can be either linear macrocyclized or polycyclized depending on the reactivity of the biosynthetic intermediates can be formed [7] With the same logic fatty acids are also biosynthesized by fatty acid synthases

moreover the PKS enzyme can be hybridized with nonshyribosomal peptide synthetase (NRPS) domains (see also ldquoNRPS metabolites and peptidesrdquo in the ldquoAlkaloidsrdquo secshytion) leading to the acylation of an amino acid by the (C

2)

n

acyl intermediate As previously the functionalization of the acyl chain depends on the PKS enzyme and the PKSNRPS products are also extremely diversified (eg hirsutellone B Fig 12) [8]

1152 Terpenes Terpenes are derived from the oligoshymerization of the C

5 isoprene units DmAPP and IPP Both

precursors are prompt to generate either an allylic cation (the diphosphate is a good leaving group) or a tertiary carbocation respectively which makes the IPP easy to react with DmAPP (Scheme 14) This reaction happens in the active site of a terpene synthase which activates the deparshyture of the diphosphate group from DmAPP thanks to Lewis acid activation (a metal like mg2+ mn2+ or Co2+ is present in the enzyme active site [9]) This leads to geranyl (C

10

monoterpene precursor) or farnesyl (C15

sesquiterpene precursor) diphosphate depending on the location of the enzyme (chloroplast for the mEP pathway or cytosol for the mVA pathway) Geranylgeranyl (C

20 diterpene) and

Constructionreactions

Decoration reaction(functionalization)Building

blocksNatural product

frameworksNatural products

HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450

P450 P450 Oxidativeauxiliaryenzymes

Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)

10-Deacetylbaccatin III

DMAPP

IPPand electrophilic

cyclizations

SCHEME 13 (a) From building blocks to natural products and (b) the example of 10‐deacetylbaccatin III


farnesylfarnesyl (C30

triterpene precursor) diphosphates can also be obtained by further additions of IPP leading to longer linear intermediates

The cyclization of linear precursors is achieved by speshycialized cyclases which generate a poorly functionalized natural product framework [10 11] Auxiliary enzymes such as oxygenases then increase the complexity and the diversity

of compounds by further functionalization (Scheme 13b) [12] A high degree of oxidation can be observed in comshypounds like thapsigargin paclitaxel or bilobalide (Fig 13) The biosynthesis of this last compound for example involves a high oxygenation pattern two Wagnerndashmeerwein rearrangements and several oxidative cleavages leading to the loss of five carbons The resulting natural products can

KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O

Claisen condensation (ndashCO2)

reduction (NADPH)

dehydration (ndashH2O)

+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H

Hirsutellone B(mixed PKSNRPS

product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol

From ahexanoylstartingblock

H

H

Fromtyrosine

H

1C lost fromdecarboxylation

FIGURE 12 Chemical logic of polyketide construction leading to variable functionalization of the elongated acyl chain and examples of resulting chemical diversity ACP acyl carrier protein DH dehydratase ER enoyl reductase KR ketoreductase KS ketosynthase mAT malonyl acyl transferase TE thioesterase

DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

Geranyl diphosphate (GPP)2 times IPP

H H

Geranylgeranyl diphosphate (GGPP)

Examplesverticillane

casbanetaxane

phorbol

Exampleslabdane

pimaranekauraneabietane

aphidicolanegibberellane

IPP

SCHEME 14 Early assembly of C5 units in terpene biosynthesis leading to diterpenes (C

20)


thus be extremely modified with structures whose biogenetic origin is far from being obvious at first sight and cannot be determined without further experiments such as isotopic labeling

1153 Flavonoids Resveratrols Gallic Acids and Further Polyphenolics We have previously discussed the polyketide origin of some phenolic compounds based on the (C

2)

n motif Other polyphenols like gallic acids are directly

derived by the aromatization of shikimic acid (C6C

1 building

block Scheme 12) [13] The C6C

3 building blocks are availshy

able from the conversion of phenylalanine and tyrosine into cinnamic and p‐coumaric acids respectively and then by further hydroxylation steps (Scheme 15) These can dimerize into lignans (eg podophyllotoxin) [14 15] through radical processes or converted to low molecular weight compounds like eugenol coumarins or vanillin [16] The coenzyme A thioesters of these C

6C

3 acids can be used as initiator units

by specialized ketosynthases for an elongation by two acetyl units leading to aromatic polyketides like styrylpyrones or diarylheptanoids (eg curcumin) [17] Important comshypounds from this metabolism are flavonoids (C

6C

3C

6) [18]

and stilbenoids (C6C

2C

6) (a decarboxylation occurs during

the aryl cyclization) [19] which are synthesized by chalcone synthase and stilbene synthase respectively Flavonoids (eg catechin) and stilbenes (eg resveratrol) are present in large amounts in fruits and vegetables and may exert their radical scavenging properties in vivo

1154 Alkaloids Alkaloids are nitrogen‐containing compounds The nitrogen(s) can be involved in an amine function conferring basicity to the natural product (like ldquoalkalirdquo) or in less or nonbasic functions such as an amide a nitrile an isonitrile or an ammonium salt (quaternary amines) For amines protonation often occurs at physiological pH and may condition their biological activity In many cases the nitrogen is biogenetically derived from an amino acid We will thus discuss alkaloids according to their amino acid origin

Alkaloids Derived from the Krebs Cycle (Lysine and Ornithine Derived) As shown previously (Scheme 12) the Krebs cycle is a crucial metabolic process which leads to α‐ketoacids (oxaloacetic and 2‐oxoglutaric acids) Their enzymatic transamination affords the two amino acidsmdashaspartic acid and glutamic acidmdashwhich are the direct biosynthetic precursors of amino acids lysine and ornithine respectively These in turn produce cadaverine a ldquoC

5Nrdquo unit

and putrescine a ldquoC4Nrdquo unit which are major components

for the biosynthesis of important alkaloids as will be discussed later (Scheme 16) Additionally ornithine is a precursor of arginine another important amino acid

ornithine‐derived alkaloids (incorporating the c4n

unit) Putrescine is derived from the decarboxylation of ornithine and is a precursor of linear polyamines like spermshyine After enzymatic methylation of one amine of putrescine

C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc

MeO2CLoganin (iridoid)

H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH

Bilobalide(highly rearrangedand missing 5 C)

CleavageH

Highoxidativecleavages

HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH

OHFrom PHE Paclitaxel

C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM

FIGURE 13 Chemical diversity in the terpene series (Wm Wagnerndashmeerwein shifts lost carbons bold bonds are remnant of primary building blocks)


in the presence of S‐adenosylmethionine transamination of the other affords γ‐(N‐methylamino)aldehyde [20] The resulting cyclic iminium is a key intermediate in the formation of many medicinally important alkaloids such as

the plant‐derived compounds cocaine atropine or the calysshytegines [21 22] Indeed this iminium is a mannich acceptor which can react with various nucleophiles the first of those being the carbanion of acetyl‐CoA Thus after a stepwise

CO2H

RCinnamic acid (R=H)p-Coumaric acid (R=OH)

RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe

C mdash C andor C mdash Oradical couplings

After E Zisomerization

for example Podophyllotoxin

O ORO

Coumarins(eg scopoletin)

[O]

Prenylationcyclizationcleavage[O]

O OO

Furocoumarins(eg psoralen)

RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe

n = 3 avonoids(from chalcone synthase)

C6C3

H

H H

From AcCoA

O

n = 3 stilbenoids(from stilbene synthase)

HO

OH

OHFrom AcCoA From AcCoA(ndashCO2)

Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA

SCHEME 15 The phenylpropanoid biosynthetic pathways

LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG

n = 1 spermidinen = 2 homospermidine

NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H

SCHEME 16 Lysine‐ and ornithine‐derived alkaloid biosynthetic pathways (mind the structural similarities)


elongation by two AcCoA units either decarboxylation can occur leading to the acetonylpyrrolidine hygrine or a secshyond mannich reaction by the intramolecular attack of the acetoacetate anion onto an oxidation‐derived pyrrolinium leading to the tropane skeleton (tropinone) The acetoacetyl‐CoA intermediate can also react intermolecularly with another pyrrolinium cation leading to cuscohygrine after decarboxylation Finally the pyrrolizidine alkaloids [23] are derived from homospermidine which when submitted to terminal oxidative deamination leads to the bicyclic skelshyeton of retronecine and further Senecio alkaloids We can mention herein that ornithine is a biosynthetic precursor of arginine bearing a guanidine function which is an intermediate toward the toxic compounds tetrodotoxin and saxitoxin (not shown)

lysine‐derived alkaloids (incorporating the c5n

unit) From lysine to piperidine alkaloids the biosynthetic steps parallel the one previously described from ornithine Indeed the oxidative deamination of cadaverine affords a δ‐amino aldehyde which cyclizes through imine formation into piperideine Protonation results in a mannich acceptor which is able to react with various nucleophiles such as β‐ketothioester anions The first product of these reactions is pelletierine which can further react through an intramolecular mannich

reaction leading to pseudopelletierine Quinolizidines [24] can also be formed first from the mannich reaction of the piperideine acceptor with the corresponding enamine nucleoshyphile and then after additional transformation steps leading for example to lupinine sparteine or cytisine

Indolizidine alkaloids [15] such as castanospermine and swainsonine are formed from pipecolic acid an amino acid derived from lysine which can be elongated by malonyl‐CoA followed by ring closure When protonated these alkaloids are oxonium mimics strongly inhibiting glycosidases

Tyrosine‐ and Phenylalanine‐Derived Alkaloids Tyrosine and phenylalanine amino acids are bearing the phenylshyethylamine moiety of many medicinally relevant alkaloids Further hydroxylations on the aromatic carbocycle or on the aliphatic part can be observed methylations can occur on phenolic oxygens and on the amine leading to catecholamines (adrenaline noradrenaline dopamine) Arylethylamines are also usual to react with endogenous aldehydes through PictetndashSpengler reactions [25] leading to important biosynthetic intermediates (Scheme 17) like

bull Reticuline from the reaction with 4‐hydroxyphenylacetshyaldehyde toward benzyltetrahydroisoquinoline alkaloids

NH2

Phenylethylamines

RONH TetrahydroisoquinolinesRO

RʹCHO

Rʹ

NH

(CH2)n

MeO

HO

Benzyltetrahydroisoquinoline(n = 1) for example reticuline

orPhenethyltetrahydroisoquinoline

(n = 2) eg autumnaline

IntermolecularCmdashO phenol

couplings

Curarealkaloids

IntramolecularC mdash C phenol

couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine

IntramolecularCmdash C coupling

and furtheroxidative events

Rʹ derivedfrom PHE

Pictet-Spenglerreaction

TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]

GalantamineNorbelladine

Rʹ derived fromsecologanin

NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids

1ClostCmdash C cleavage

and ring extension

H

ROH

1C lost

Cleavage

SCHEME 17 Tyrosine‐derived alkaloid biosynthetic pathways (double head arrows figure bond cleavages during biosynthetic processes)


morphine berberine tubocurarine isoboldine or the highly modified aristolochic acid [26 27]

bull Automnaline from the reaction with 3‐(4‐hydroxyphenyl)propanal toward phenylethyltetrahydroisoquinoline alkaloids colchicine cephalotaxine or schelhammerishycine [28 29]

bull Ipecoside from the reaction of dopamine with secoloshyganin toward terpene tetrahydroisoquinoline alkaloids ipecoside or emetine

Lastly norbelladine (top of Scheme 17) is issued from the reductive amination of 34‐dihydroxybenzaldehyde (derived from phenylalanine) with tyramine (derived from tyrosine) and constitutes a biosynthetic node leading to Amaryllidaceae alkaloids such as galantamine crinine or lycorine depending on the topology of phenolic couplings In all these biosynthetic routes radical phenolic couplings are key reactions for CC and CO bond formations and rearrangements [30 31]

Tryptophan‐Derived Indole and Indole Monoterpene Alkaloids As for alkaloids derived from tyrosine and phenylalanine those derived from tryptophan are formed after decarboxylation of the amino acid (into tryptamine) and possible hydroxylation of the aromatic carbocycle (eg serotonin) and N‐methylation (eg psilocin) As previously tryptamine can also react through PictetndashSpengler reactions to form tetrahydro‐β‐carbolines which can be aromatized for example into harmine (Scheme 18) [16]

When the aldehyde partner of the PictetndashSpengler reacshytion with tryptamine is the terpene secologanin strictosidine is formed as an entry toward the vast monoterpene indole alkaloids [32 33] Hydrolysis of the glucosidic part releases the strictosidine aglycone bearing an aldehyde while iminshyium formation and further cyclization and reduction can lead to ajmalicine (from oxocyclization) or yohimbine (from carshybocyclization) These alkaloids are referred to as from the Corynanthe type with the monoterpene carbon skeleton unmodified Although it misses one carbon and has a very

RO

Carbonylcompounds

TRPNH

NH2

Indolethylamines(eg serotonine)

RONH

NH

Rʹ NH

N

MeOPictet-Spenglerreaction for example Harmineβ-Carbolines

NH

NHH

O

MeO2C

MeO2C

OH

H

H

Rʹ derived from secologanin

Strictosidine aglycone

NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H

Strychnine (C lost)Corynanthe type

Aspidosperma type Iboga type

N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline

Complextransformations

NH

NMe

HN

MeN

H

H

Chimonanthine

Cyclizationdimerization

Prenylationcyclization

NH

NMeHO2C

H

Lysergic acid

H

H

Ergot alkaloidsPyrroloindoles Indole monoterpene

1C lost

1C lostFrom AcCoA

SCHEME 18 Tryptophan‐derived alkaloid biosynthetic pathways (gray parts monoterpenic units)


different structure strychnine is related to the Corynanthe alkaloids incorporating two carbons from acetyl‐CoA Highly modified monoterpene skeletons are derived from the Corynanthe core through CC bond breaking and reorshyganization leading to Iboga‐type (eg catharanthine) and Aspidosperma‐type (eg vindoline) alkaloids The antishycancer drug vinblastine is a heterodimer resulting from the nucleophilic attack of vindoline on a mannich acceptor resulting from catharanthine found in madagascar perishywinkle (Catharanthus roseus) The heteroaromatic comshypounds ellipticine camptothecin and quinine are also derived from a Corynanthe‐type precursor although in this case the biosynthetic relationship may not be obvious due to deep modifications of the skeleton

Finally two important classes of compounds have to be mentioned since they have inspired many synthetic chemists The pyrroloindole alkaloids result from the cyclization of tryptamine as found in physostigmine (formed by a cationic mechanism after methylation in position 3 of the indole not shown) or in chimonanthine (presumably formed by a radical coupling mechanism Scheme 18) The ergot alkaloids are derived from the 33‐dimethylallylation on position 4 of the indole in trypshytophan whose further cyclization and oxidation processes afford the natural products (eg lysergic acid Scheme 18 and ergotamine) which have had important medical applications [34]

NRPS Metabolites and Peptides NRPS enzymes assemble amino acids including nonproteinogenic ones into oligopeptides The enzymes contain several modules and especially an adenylation domain (A) which specifically selects and activates the amino acid to be transferred as a thioester on the nearby peptidyl carrier protein (PCP) [2] A condensation module (C) then catalyzes the formation of the peptide bonds between the newly introduced amino acyl‐PCP (bearing a free amine) and the elongated peptidyl‐PCP thioester At the end of the elongation a cyclization can occur into cyclopeptides but the peptide can also be

transferred to auxiliary enzymes like methyltransferases glycosyltransferases or oxidases (vancomycins are typical products of such functionalizations) [35 36] The formation of heterocycles is also frequently encountered in this metabolism as in penicillins that are derived from the tripeptide α‐aminoadipoyl‐cysteinyl‐valine or telomestatin (Fig 14) [2]

Other Alkaloid Origins There are many other nitrogen sources involved in alkaloid biosyntheses for example nicotinic acid (originated from aspartic acid and intershymediate in nicotine and anabasine biosyntheses) and anthranilic acid (originated from tryptophan and intermedishyate toward acridines or aurachins) The amination reaction (eg through transamination of carbonyl compounds) is also a way to introduce nitrogens in natural products for example from fatty acids steroids (toward Solanum alkaloids or cyclopamines) or other terpenoids (aconitine and atisine have diterpene skeletons while Daphniphyllum alkaloids are triterpene derivatives) Finally nucleic acids can also be precursors of alkaloids like the well‐known caffeine

12 FROM BIOSYNTHESIS TO TOTAL SYNTHESIS STRATEGIES TOWARD THE NATURAL PRODUCT CHEMICAL SPACE

121 The Chemical Space of Natural Products

Natural products occupy an important place in human com munities as demonstrated by their vast use from ancient times to nowadays like dyes fibers oils pershyfumes agrochemicals or drugs Broadly both primary and secondary metabolites could be classified as natural products while the latter as discussed previously are usushyally regarded as the ldquonatural productsrdquo owing to their comshyplexity and diversity arising from a variety of biosynthetic pathways The structural chemical diversity found among

N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes

FIGURE 14 Structural diversity of nonribosomal peptide compounds (AAA α‐aminoadipic acid)

FROm BIOSyNTHESIS TO TOTAL SyNTHESIS STRATEGIES TOWARD THE NATuRAL PRODuCT CHEmICAL SPACE 11

all living organisms defining the chemical space of natural products [37] is the consequence of their evolution occurshyring as an adaptation of organisms to their environment It is commonly believed that secondary metabolites are proshyduced as messengers by living organisms or as weapons against enemies and thus they should have certain biological activities in a medicinal point of view [38] Indeed natural products are regarded as one of the main sources of medicines (Fig 15) From the traditional medicinal extracts to every single bioactive molecule the methods of extraction purification identification and biological investigation of natural products have been well established Their complex structures and interesting properties have attracted synthetic chemists to accomplish their total syntheses and that of medicinally relevant anashylogs sometimes in the industrial context [39] Thus tarshygeting the chemical space of natural products has never been more relevant than today Although the discovery of natural products demands time and labor‐consuming manipulations it is worth to notice that the knowledge on this chemical space is still continually growing while biological advances allow for discovering and undershystanding potential targets However increasing the chemical space of human‐made compounds based on natural products should benefit from transdisciplinary colshylaborations such as the use of coupled biosynthetic and chemical synthetic methods to design original ldquounnatural natural productsrdquo [40]

122 The Biosynthetic Pathways as an Inspiration for Synthetic Challenges

1221 Precursor‐Directed Biosyntheses and Mutashysynthetic Strategies to Increase the Chemical Space of Natural Products As the genetics and biochemistry of natural product biosynthesis are better understood novel biosynthetic techniques have been developed to study and generate new diversity in natural product analogs (Scheme 19) Precursor‐directed biosynthesis (PDB) is considered as the earliest example of combining chemical and biological methods for the generation of complex natural product analogs [41 42] This approach compared with the biosynthetic pathway of wild‐type metabolites (Scheme 19a) involves the feeding of analogs of the natural biosynthetic building blocks to the living organisms (Scheme 19b) usually bacteria or fungi which incorporate the modified precursors into the biosynthesized compound mutasynthesis also termed as mutational biosynthesis (mBS) involves the inactivation of a key step of the bioshysynthesis in a mutant microorganism (Scheme 19c) which can then be fed by various modified or advanced building blocks (mutasynthons Scheme 19d) [43] These mutasshyynthons could not be incorporated by the wild type due to specificities of the enzymatic machinery Build up on PDB mBS eliminates the natural biosynthetic intermediate thus generating a less complex mixture of metabolites and making the purification or yield of target products better

O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO

Micafunginantifungal

Rapamycinimmunosuppressive

Galantamineanti-Alzheimer

Taxolanticancer

Artemisininantimalarial

Vancomycinantibiotic

FIGURE 15 Some famous natural products currently used as drugs


Both approaches can potentially greatly increase the divershysity of natural compounds

1222 The Biomimetic Strategy A Bridge between Biosynthesis and Total Synthesis During the past century synthetic chemists were endeavoring to discover more effishycient strategies to access complex natural products The chemical synthesis of tropinone by Robinson in 1917 [44] one of the first biomimetic ones is a fantastic example of an early efficient synthesis which consisted in a multicomposhynent process between succinaldehyde methylamine and calcium acetonedicarboxylate [45] Since then the conshystruction of natural products by chemical methods inspired by naturersquos biosynthetic pathways has attracted many synthetic chemists and participated in the progress of organic chemistry As discussed in the book Biomimetic Organic Synthesis coedited by one of us (BN) an increasing number of total syntheses have been termed ldquobiomimeticrdquo or ldquobioinshyspiredrdquo during the last 20 years meaning the use of a synthetic tactic that follows or mimics a hypothetical or proven biosynthetic pathway Concomitantly the biosynshythesis of natural products has been more and more undershystood thanks to genetic and enzymatic studies Therefore as a bridge between biosynthesis and total synthesis biomishymetic synthesis is able to overcome some drawbacks of conshyventional strategies as it often relies on the self‐assembling properties of a key reactive intermediate [46]

Tremendous works dealing with bioinspired total synshytheses of secondary metabolites have thus been achieved providing new insights in the reactivity of biomimetic precursors and occasionally leading to controversy or

unresolved questions [47] An interesting example goes to hirsutellones a family of fungal PKSNRPS compounds (also regarded as alkaloids due to their nitrogen) with intriguing structures and a significant antitubercular activity [7] Their biosynthesis has been hypothesized by Oikawa who proposed a key linear precursor of the related compounds GKK1032A

2 made from one tyrosine nine

AcCoA and several methylations by S‐adenosylmethionine [48] We applied this hypothesis to the less methylated hirsutellones (Scheme 110) Two different biosyn thetic pathways can be proposed for the polycyclization Pathway (a) involves the selective oxidation of one of the dienoyl double bonds (CγCδ) to generate an epoxide and of the phenol This ldquoelectrophilic headrdquo would then be attacked in a conjugated ene reaction involving the triene and initishyating the cyclization Formation of the bent paracycloshyphane would then be followed by a stereoselective intramolecular DielsndashAlder (ImDA) reaction leading to the complete tricyclic core of the natural product Pathway (b) involves the allylic oxidation at the terminal methyl group of the triene to release an allylic alcohol or cation as an ldquoelectrophilic tailrdquo The polycyclization would then be initiated through reverse electronic activation compared to pathway (a) forming the first cyclohexane ring before the ImDA reaction occurs

Nicolaou et al [49] and uchiro et al [50] achieved the total syntheses of hirsutellone B in 2009 and 2011 respecshytively We recently described a formal total synthesis by forming the key decahydrofluorene (tricyclic) core of hirsutellone in a biomimetic strategy following pathway (b) [47] As for the synthesis of this important synthetic

E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)

Usually as a mixture with the wild-type intermediates depending on

enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

The AndashB intermediate is notproduced the biosynthesis is blocked

Blocked mutant

E1

(d)

E2 E3A

A

B

C

The mutasynthon B replaces themissing natural intermediate B

and is incorporated in the productBlocked mutant

E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4

SCHEME 19 (a) Biosynthetic pathway of wild‐type metabolites (b) precursor‐directed biosynthesis the modified synthon B replaces the natural synthon B (c) biosynthetic pathway blocked by a mutation (the enzyme E4 is not functional) (d) mutasynthesis a mutasynthon B is introduced to replace B and is incorporated in the biosynthesis leading to a ldquomutatedrdquo natural product




Edited by












10 9 8 7 6 5 4 3 2 1



PREFACE xv







References 16




References 40

CONTENTS

viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4




Edited by












10 9 8 7 6 5 4 3 2 1



PREFACE xv







References 16




References 40

CONTENTS

viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4












10 9 8 7 6 5 4 3 2 1



PREFACE xv







References 16




References 40

CONTENTS

viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4




PREFACE xv







References 16




References 40

CONTENTS

viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4



PREFACE xv







References 16




References 40

CONTENTS

viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


viii CoNtENtS





References 126








5 158








CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


CoNtENtS ix















x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


x CoNtENtS








References 294






References 328








CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


CoNtENtS xi




















xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


xii CoNtENtS





References 517






INDEX 548


































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4



































Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4















Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4





Preface






xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


xvi PrEfACE




Thessaloniki Greece



111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4




111 Definitions
















1





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4





6C

3

units) and C6C






chemistry












PS-I

PS-IIendash

hν H2O H+ and O2

ATP synthase

NADP reductase

H+ (gradient)

H+ADP + Pi ATP

NADPHH+NADP+

H+


Chloroplaststroma

Thylakoidmembrane



CO2

RuBP

Rubisco


ATP

ADP3-PGAL

NADPHH+

NADP+

(Calvin cycle)


Chloroplaststroma

CH2OPO32ndash


2ndash



CH2OPO32ndash

OOH

HO

HOO

HO

HO2CCO2H

HO

CO2PO32ndash

HO

CHOHO

endash

Cytosol






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4






10 C

20 and C







C15

and C30








2 or



CHOHO

CO2H

O

CH2OPO32ndash


2ndash

HOOH

HO

HOH2CO

OHC

CH2OPO32ndash

OHHO

CO2H

HO

OH

OH

TYR

PHE

CO2H

NH2

TRP

CH2OPO32ndash

HO

HOH2COH

MEP


CO2HHO

SER

GLY CYS

CO2HOPO3

2ndash

CH2OH

OHHO2C

MVA


Polyketides

Krebscycle

(citric acid)

VAL ALA ILE LEU

CO2H

O

HO2C

CO2HO

CO2H

ASP

LYS

GLU

Glucose-6-phosphate



3-PGAL

OP2O63ndash OP2O6

3ndash

IPP DMAPP

3-PGA PEP PA

O SCoAAcCoA

3x

Cytosol

Cytosol

Chloroplasts

Chloroplasts

Glycolysis

C2

C5


2-Oxoglutaricacid

MET

THR

PRO

ARGORN


Aminoacids

Peptidesproteins

Phenolics

C1

C5N C4N

ldquoCH3rdquo














n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4












n linear





2CO)

nOH is formed


2 linker



2 (by enoyl



2)

n





10



20 diterpene) and





HH

OH OAcH

HO O OH

OHO

OBz

P450

P450

P450

P450


Taxadiene

OP2O63ndash

OP2O63ndash

3times

(a)

(b)


DMAPP


cyclizations







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4







KS

S-ACP

O O

KR

S-ACP

OH O

S-MAT

O

YesNo

R

R

R

YesNoDH

S-ACP

OR

YesNoER

S-ACP

OR

YesNoTE

OH

OR

New cycle

New cycleor

release

New cycleor

release

New cycleor

release

Release

R in

crem

ente

d by

two

carb

ons

HO

O

S-ACP

O


reduction (NADPH)


+

reduction (NADPH)

hydrolysis (H2O)

O O NH

OH

OH

H H

H H


product)

OO

O

OHOH

HO OH

Norsolorinic acid

O

O

O

O CHO

OH

HH

H

H

HH

OHHemibrevetoxin B

OOHO

OHO

HOHO OH

Erythronolide A

OH

OH

HO

Panaxytriol


H

H

Fromtyrosine

H



DMAPPOP2O6

3ndashOP2O6

3ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash

OP2O63ndash


H H



casbanetaxane

phorbol

Exampleslabdane



IPP


20)




2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4





2)



1 building




6C



6C

3C

6) [18]


2C





5Nrdquo unit





C10 C15

C15

C10

C10

C30

CO2H

Chrysanthemic acid

OH

Menthol

O

HO

H

HOGlc


H

H

H

HH

OO

OParthenolide

O

O

OHOHO

OAcHO

OnC3H7

O

O

O

nC7H15

Thapsigargin

O

O

OO

H

H

O

Cleavage

H

H

Artemisinin

C20 C40

O

O

OO

OO

OHOHH


CleavageH


HO OAcH

AcO O OH

OOOBz

O

Ph

BzNH


C25O

H

HO

OHCH

OH Ophiobolin A

H

HO

H

H

HHCholesterol

(missing 3 C WM)

H

H H H

H

H

Hopene

β-Carotene

C30 - 3

C15

C20 - 5WM

WM





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4





CO2H


RO

PHETYR

OH

[H] [O]

lignans

OH

O

O

O

O

OMeMeO

OMe




O ORO


[O]


O OO


RO

nAcetyl-CoA

thencyclization

n = 2 styrylpyrones

O O

OMe


C6C3

H

H H

From AcCoA

O


HO

OH


Resveratrol

HO

OH

OH

OH

OH

H

Catechin

MeO Yangonin

From AcCoA


LYS

CO2

Cadaverine

O NH

H2O

NH

Piperideineiminium

Pelletierine

AcAcCoA

CO2

NH

O

N

O

Pseudopelletierine

NH

Ph

OH

Ph

O

Lobeline

NH

δ+

δndash

N

H

H

N

H

OH

Lupinine

N

H N

H

(+)-Sparteine

N

NH

O (ndash)-Cytisine

NH

CO2H

Pipecolic acid

N

OHHO

OH

HO

H

Castanos permine

ORN

CO2

NH2 NH2 NH2 NH2

NH2

NH2

NH2

PutrescineO

NHMe

N-Methylpyrrolinium

2 timesAcCoA

NMe

ARG


NMe

O

HygrineCO2

CO2

MeN

O

[O]

TropinoneCO2

HNHO

OHOH

OH

Calystegine B2

MeN

OAtropine

O

Ph

HO

NMe

NMe

NMe

O

Cuscohygrine

HN

HN

NH2

( )n

O

n = 2

N

HHO

Retronecine

HH

H

H

H

HO

H H

H










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4










NH2

Phenylethylamines


RʹCHO

Rʹ

NH

(CH2)n

MeO

HO





couplings

Curarealkaloids


couplings

ONMe

HHO

H

HO

Morphine

NMe

MeO

HO

MeOOH

Isoboldine

O

O

OMe

NO2

CO2H

Aristolochic acid

OMe

O

NHAcMeO

MeOMeO

Colchicine

N

O

O

OMe

OMeBerberine



Rʹ derivedfrom PHE


TYR

HO

HO CHO

HNHO

HO

OH

OMeO

OH

NMe

[O]



NAc

HO

HO

O

CO2MeH

H

H

OHIpecosideaglycone

Ipecac alkaloids


and ring extension

H

ROH

1C lost

Cleavage









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4









RO

Carbonylcompounds

TRPNH

NH2


RONH

NH

Rʹ NH

N


NH

NHH

O

MeO2C

MeO2C

OH

H

H



NH

N

OH

H

H

Ajmalicine

N

N

O

O

H

H

H



N

N

OH

OMe

Quinine (C lost)

N

NH CO2Me

Catharanthine

NH

N

CO2MeH

OAc

OH

Vindoline


NH

NMe

HN

MeN

H

H

Chimonanthine



NH

NMeHO2C

H

Lysergic acid

H

H


1C lost

1C lostFrom AcCoA











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4











N

S

CO2HO

HNPhH2C

O

Penicillin G

OH

HN

HN

O

O

ONH2

O

OHO

NHMe

OCl

O

NH

NH

NH

O

ClHO

O

HN

H

H

HOOH

OHHO2C

Vancomycin aglycone

ON

NO

O

NN

O

O

N

N O

Me

S

N N

OMeH

Telomestatin

L-AAA-L-CYS-D-VAL

Enzymes






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4






O NH

OHO

O

OO

O

O

OH

HOO

O O

OH

HOO

NH ONH2

O

ONH

NH

O

OCl Cl

O

O

OH

HN

HN

HN

HN

OO

HO

HN

OH

OHOH

O

O

HO

HO

OHO

O

OHH2N

O

OH3C

H

O

H

CH3

CH3

H

O O

NO

H

O

HO

O

NO

O

NH

HN

OHO

HONH

ON

H

HO

O

H2N

O OH

ONH

OH

ON OHO

OH

HO OS OH

OOOH

OHO

O

ON

OO

O

HO

O

O OH

OO




Taxolanticancer












E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4










E1

(a)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ

E1 E2 E3A

A

B

B CC

B

A AʹBʹCʹ

(b)


enzyme specicity

E1

(c)

E2 E3A

A

B

B CC

B

A AʹBʹCʹ


Blocked mutant

E1

(d)

E2 E3A

A

B

C



E4D

BE4

D

E4D B

BD

C

B

A AʹBʹCʹ

A

B+

C

B

A+

AʹBʹCʹ

+

E4


Documents

Thumbnail - download.e-bookshelf.de · 1.2 From Biosynthesis to total Synthesis: Strategies toward the Natural Product Chemical Space, 10 1.2.1 the Chemical Space of Natural Products,